Methamphetamine (meth) use and binge drinking (defined for men as drinking five or more drinks on one occasion) are associated with significant morbidity and mortality. The economic cost of meth use and binge drinking in the US exceeds $23 and $170 billion, respectively. Among MSM, meth use and binge drinking are up to 20 and 3.5 times more prevalent than in the general U.S. adult population, respectively. Moreover, these two substances are consistently associated with unprotected sex and HIV seroconversion among MSM, who comprise over half of the new infections in the U.S. Thus, effective interventions to reduce meth use and binge drinking may also function as an important HIV prevention strategy by reducing substance-related HIV risk behavior. Naltrexone, a u-opioid receptor antagonist, is a promising agent for meth-using and binge-drinking MSM. Naltrexone has shown efficacy in reducing relapse to amphetamines and is FDA-approved for alcohol dependence. Oral naltrexone is inexpensive and has few toxicities but the standard daily regimen for naltrexone is problematic as patients forget to take the medication. Given the challenges in daily dosing, alternate regimen schedules have been proposed to increase efficacy and expand the population that may benefit. One approach is intermittent targeted administration of naltrexone, whereby individuals take the medication as needed in anticipation of substance use or during periods of craving. Administration of naltrexone prior to exposure to amphetamines significantly attenuates craving and targeted naltrexone has shown efficacy in reducing heavy alcohol use. However, there have been no studies assessing intermittent targeted dosing of naltrexone among meth-using and binge-drinking MSM. Polysubstance use patterns are common among MSM-studies among those who take more than one substance are urgently needed. The aims of this study are to determine whether targeted dosing of naltrexone is feasible, tolerable and acceptable among non-dependent meth-using and binge-drinking MSM. Design: This is a pilot, double-blind, placebo-controlled trial of targeted oral naltrexone. Thirty non-dependent, episodic meth-using and binge-drinking MSM will be randomly assigned to receive 8 weeks of naltrexone 50 mg or placebo, to be taken on an as-needed basis to attenuate meth craving or reduce binge drinking. Participants will be seen bi-weekly to receive study drug and substance use counseling. Safety assessments and behavioral surveys will be completed at bi-weekly and monthly visits. Feasibility, tolerability, and acceptability (Specific Aims 1-3) will be assessed with enrollment and retention rates, frequency of adverse events, participant evaluation of targeted dosing and medication adherence. Meth use and drinking outcomes will be assessed via daily text messages and bi-weekly timeline follow-back (Exploratory Aims). Sexual behaviors will be assessed via monthly surveys (Exploratory Aims). GEE logistic models will be used compare the proportions of MSM taking medication during periods of meth craving and binge drinking. GEE binomial and negative binomial models will be used to assess treatment effects on meth use, drinking and sexual behavior. PUBLIC HEALTH RELEVANCE: Meth use and binge drinking are linked to HIV-related sexual risk behaviors and HIV infection among men who have sex with men (MSM). This study will examine the feasibility, tolerability and acceptability of taking naltrexone on an as-needed basis during periods of meth craving and in anticipation of drinking among MSM. This study will contribute to the field of substance use and HIV prevention research for a marginalized and disproportionately impacted population.